Louis Philipson, MD, PhD

Professor, Medicine

Committee on Cell Physiology
Human Nutrition and Nutrional Biology

AB    (cum laude), Biochemistry, 
          Harvard College 

PhD    Biochemistry, University of Chicago 

MD    (with honors), University of Chicago 
          Pritzker School of Medicine

Research Summary

Studies on Ion Channels of Insulin Secreting Cells

Our goal is to develop a greater understanding of the relationship of ion channels, regulation of intracellular Ca2+ concentration, and insulin secretion in normal pancreatic ß-cells and how this process may be dysfunctional in diabetes mellitus. The work described here is among the first series of investigations to examine the expression of K+ and Na+ ion channel genes in islet cells. We have also cloned and characterized a new Ca2+ channel alpha1 subunit, which is expressed in both brain and neuroendocrine cells. 

Recently we reported the identification of cDNAs encoding delayed rectifier-type K+ channels in human insulin-secreting cells. In addition several other related K+ channel cDNAs were isolated from human genomic and skeletal muscle libraries, some of which have also been shown to be present in normal islets. In collaboration with Dr. D. J. Nelson, our expression studies in Xenopus oocytes and stable cell lines have confirmed the similarity of these currents to those observed in normal cells. We have also shown that these cDNAs encode subunits that can arrange to form active heteromultimers, which also may be an important mechanism in generating the K+ currents present in a variety of tissues, such as brain, heart, and pituitary. Antibodies directed against the channel and a fusion epitope have allowed characterization of the protein in transfected cell lines and transgenic animals. Additional studies have examined the mechanisms of subunit association and inactivation. The expression of one of the human K+ in pancreatic ß-cells of transgenic mice is associated with hyperglycemia, as anticipated. This may provide a model in which to study the role of membrane potential in glucose-induced insulin signalling. Ongoing studies include generation of K+ channel knock-out mice by a dominant-negative approach, examination of the effects of the -subunit, and expression via adenovirus vectors.

Several members of the inward rectifier class have been cloned and expressed. In collaborative studies, we have identified several new cDNAs and their genes encoding new members of this family in insulin secreting cells, including the human ROMK1 ATP-regulated inward rectifier, and GIRK1, a G-protein-linked inward rectifier. An epitope tag has been added to the GIRK1 cDNA, enabling us to study the expression of the protein as we examine its co-expression with G-protein coupled receptors.

Other studies are in progress to examine the role of Na+ and Ca2+ channels in insulin secretion. These studies have shown that a different subset of voltage-dependent Na+ channel gene isoforms (of which five are known) are expressed in islets that are in the adult brain. In a joint project with Prof. R. J. Miller we have cloned and studied the expression of a new Ca2+ channel alpha one subunit alpha 1E. This channel is expressed strongly in multiple nuclei of the brain, in pancreatic ß-cells and neuroendocrine cell lines, and has several splice variants. The intact cDNA is now being examined in several expression systems.

Some Selected Papers

Qian, F., Huang, P., Ma, L., Kuznetsov, A., Tamarina, N. and Philipson, L.H. TRP Genes: candidates for non-selective cation channels and store-operated channels in insulin secreting cells. Diabetes 51: S183-S189, 2002.

Tamarina. N., Wang, Y., Mariotto, Y., Bond, C., Adelman J., and Philipson, L.H. Small conductance calcium-activated K+ channels (SK) are expressed in pancreatic islets and regulate glucose responses. Diabetes 52: 2000-6, 2003.

Bindokas, V.P., Kuznetsov, A., Sreenan, S., Polonsky, K.S., and Philipson, L.H. Visualizing Superoxide Production in Normal and Diabetic Rat Islets of Langerhans. J Biol Chem. 278: 9796-9801, 2003.

Fridyland, L.E., Tamarina, T., and Philipson, L.H. Modelling of Ca2+ flux in pancreatic ß-cells: role of plasma membrane and intracellular stores. Am J. Physiol 285:E138-54, 2003.

Updated 12/16/02.